The compound (±)-2-[phenyl(1-methyl-1H-pyrazol-5-yl)methoxy]-N,N-dimethylethanamine, also referred to as (±)-5-[α-(2-dimethylaminoethoxy)benzyl]-1-methyl-1H-pyrazole, or Cizolirtine, of the formula
is described in the European Patent EP 289 380. This compound is a potent analgesic which is currently in phase II clinical trials. Optical resolution by fractional crystallization with optically active acids has been applied to the Cizolirtine racemate (International Patent Publication WO 99/02500). The study of their analgesic activities has shown that the dextrorotatory enantiomer, (+)-Cizolirtine, is more potent than the (−)-Cizolirtine.
A further family of active compounds wherein a thiophene ring is present instead of the phenyl ring has been described in International Patent Publication WO 99/52525. Among them, the compound (±)-2-[thienyl(1-methyl-1H-pyrazol-5-yl)methoxy]-N,N-dimethylethanamine, of formula (I)
is currently in clinical trials for the treatment of depression. It can be prepared by O-alkylation of the compound of formula II:

The carbinols such as the one of formula II are key intermediates to reach the compounds described in International Patent Publication WO 99/52525. The pure enantiomers of (+)-I and (−)-I may be prepared by separately O-alkylating the enantiomerically pure intermediates (+)-II and (−)-II. Thus, a synthetic process to the enantiomerically pure/enriched intermediates (+)-II and (−)-II is needed.
The enantioselective reduction of prochiral ketones has been proposed in organic synthesis to obtain secondary alcohols with high enantiomeric purity. Accordingly, a number of strategies for the asymmetric reduction of prochiral ketones to single enantiomer alcohols have been developed [R. Noyori, T. Ohkuma, Angew. Chem. Int. Ed., 2001, 40, 40–73, Wiley-VCH Verlag]. However, no procedure has been described yet for methanols substituted with two heterocycles.
A phenyl transfer reaction to aryl aldehydes as an approach towards enantio-pure diarylalcohols has also been proposed, as alternative to the enantioselective reduction of prochiral ketones [P. I. Dosa, J. C. Ruble, G. C. Fu, J. Org. Chem. 1997, 62 444; W. S. Huang, L. Pu, Tetrahedron Lett. 2000, 41, 145; M. Fontes, X. Verdaguer, L. Solà, M. A. Pericàs, A. Riera, J. Org. Chem. 2004, 69, 2532]. For this transformation, the group of Bolm et al. developed a protocol that utilizes a ferrocene-based ligand (or catalyst) and diphenylzinc in combination with diethylzinc as an aryl source [C. Bolm, N. Hermanns, M. Kesselgruber, J. P. Hildebrand, J. Organomet. Chem. 2001, 624, 157; C. Bolm, N. Hermanns, A. Classen, K. Muñiz, Bioorg. Med. Chem. Lett. 2002, 12, 1795]. Enantiomerically enriched diarylmethanols with excellent enantiomeric excess (up to 99% ee) were thus obtained in a straightforward manner. Subsequently, the applicability of air-stable arylboronic acids as an aryl source was also demonstrated [C. Bolm, J. Rudolph, J. Am. Chem. Soc. 2002, 124, 14850]. However, these systems require a high catalyst loading (commonly ˜10% mol.) to achieve such high enantioselectivity. With the aim of reducing this problem, the use of triphenylborane was recently proposed as an alternative phenyl source in a reaction where the ferrocene-based catalyst is also used (J. Rudolph, F. Schmidt, C. Bolm, Adv. Synth. Catal. 2004, 346, 867). It has been applied with difficulties to heteroaromatic aldehydes, for example to 2-thiophenecarbaldehyde.
However, there are still some difficulties to obtain chiral alcohols with a high yield and enantioselectivity without a high amount of catalyst. For their large-scale preparation, the application of highly efficient catalytic systems and enantioselective methods employing inexpensive starting materials and simple purification steps would be most desirable.
On the other hand, the application of these processes to heteroaryl systems is challenging. There is at the present time no example of an enantioselective addition of thienyl- or phenylzinc reagents to heteroaryl aldehydes which comprise one or two nitrogen atoms, such as methyl-pyrazol aldehyde. This is understandable, since substrates containing a nitrogen heteroatom can be expected to form catalytically active complexes (or product complexes) which would usually drastically diminish the selectivity by favoring competing catalytic pathways. Indeed, it is well known in zinc chemistry that various functional groups like esters or nitriles are tolerated on the aldehyde substrates. However, Lewis basic or coordinating functional groups often lead to drastic decreases in enantioselectivity in arylzinc addition reaction, due to their ability to complex to the zinc reagent or the active catalyst. An extreme example of this behavior would be the asymmetric autocatalysis in the addition of zinc reagents to aldehydes as examined by Soai et al. (T. Shibata, H. Morioka, T. Hayase, K. Choji, K. Soai J. Am. Chem. Soc. 1996, 471).
Thus, to attain satisfactory ee values by an enantioselective addition reaction, an appropriate coordination of the catalyst system and the aldehyde is required. The results with unusual substrates cannot be predicted, and each addition has to be investigated separately with regard to the substrate.